This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. B cells that display autoreactive B cell receptors (BCR) are typically deleted or anergized. Human B cells that productively rearrange the Ig VH4-34 gene segment are commonly identified among autoimmune and lymphomagenic B cell populations, yet they routinely escape BCR-induced clonal deletion. Specific survival mechanism(s) employed remain unknown, however altered BCR signaling patterns (threshold, duration, perpetuation of signal cascade) have been proposed as likely candidates. CD45 is a protein tyrosine phosphatase present on lymphocytes, and is centrally involved in antigen receptor signaling when in its active, monomeric form. Interestingly, VH4-34+ antibody against self I/i-antigen is also crossreactive with CD45. Here, we hypothesize that recognition of surface CD45 by VH4-34 Ab should promote CD45 dimerization and inactivation. As a consequence, normal BCR signaling properties should be altered, potentially generating a developmental/differentiation state that is conducive to autoimmune/neoplastic progression.